PROJECT SUMMARY Prior research has demonstrated a consistently strong inverse association between statin drug use and risk of developing lethal prostate cancer, and a stronger protective effect with a longer duration of use. Further, in men with clinically localized prostate cancer, statins are associated with a reduced risk of progression to metastasis and dying from prostate cancer. For statins to have clinical utility as chemopreventive and therapeutic (adjuvant) agents, additional characterization of the mechanisms through which statins interact with the tumor microenvironment is needed. Yes-associated protein (YAP) is a transcriptional regulator highly expressed in regulatory T lymphocytes (Tregs). Statin drugs have been shown to inhibit YAP nuclear translocation (via YAP phosphorylation) required for Foxp3-meditated Treg immunosuppressive function. Thus, we propose to investigate the association between statin drugs and YAP-mediated Treg dysfunction, a novel immune-modulatory mechanism through which statins may impede development and progression of lethal prostate cancer in the following specific aims. For Aim 1 (K99 phase) we will create a new tissue microarray set including statin users and nonusers at the time of prostatectomy matched on clinical pathological characteristics. We will evaluate whether the proportion of Tregs with phosphorylated YAP in the cytoplasm of Tregs differs between statin users and nonusers, and if the prostate immune cell profile differs among statin users and nonusers. For Aim 2 (R00 phase), we will conduct a proof-of-principle randomized trial investigating the effect of statins on YAP-mediated Treg dysfunction in men diagnosed with prostate cancer scheduled to receive prostatectomy. This proof-of-principle trial will also provide a controlled environment to assess the effect of a single type of statin and dosing schedule to overcome heterogeneity in the type of statin drugs and dose in the observational study purposed in Aim 1. Potential biases, such as confounding by indication, will be minimized through the use of randomization. We will leverage the tremendous expertise in the biology and measurement of the immune cell profile present in prostate cancer tissue and our established, well characterized prostate cancer cohorts with associated archived tissue at JHU. The translational value of this work lies in the ability to characterize the effect of statin drugs on a novel immunemodulatory mechanism, which may be relevant in the setting of immune-based therapy for prostate cancer. This research plan is complemented by a training plan that builds on the applicant?s background in cancer epidemiology and research synthesis methods and includes new training in 1) contributing an epidemiologic perspective in multidisciplinary team science collaborations; 2) conducting tissue-biomarker validation studies; and 3) clinical trial design and implementation. The combined research and training plans will prepare the applicant for a successful independent research career focused the translation of cancer biomarkers into improved population health outcomes.